A hundred years ago the major cause of illness was infection. Today a major cause of illness is stress related. Chronic stress affects the hypothalamic-pituitary-adrenal axis and the secretion of glucocorticoids, resulting in neurotoxic effects that play an important role in the brain changes seen in depression and in post traumatic stress disorder.
Psychiatric disorders are debilitating conditions that impair the productivity of otherwise physically healthy individuals. Often, the development is gradual and symptom severity increases undetectably until an individual's functionality is impaired. As an example, chronic severe posttraumatic stress disorder (PTSD) is a common psychiatric disorder with an estimate lifetime prevalence of 7.8%. In certain populations, such as Vietnam combat veterans, the rate of PTSD is 30%. PTSD resulting from early physical and/or sexual abuse is a highly prevalent psychiatric condition in women. PTSD causes persistent functional impairment and emotional distress and generally shows only a limited response to current available psychopharmacologic treatments. Studies also indicate that PTSD will develop in 15% to 25% of trauma victims. Recent studies have shown that physical injury, over and above exposure to the traumatic event increases the risk of PTSD (Koren, Am J Psychiatry, 2005; 162:276-282). Certain types of trauma are associated with a very high rate of subsequent development of PTSD. An example of this is rape. PTSD has been shown to occur in 50% of women and 65% of men following rape.
Time-limited responses develop in a large proportion of trauma victims during the first 48-72 hours (acute stress reaction) and to a lesser extent over the first 4 weeks (acute stress disorder). The presence of Acute Stress Disorder signals a need for an immediate preventive intervention since the likelihood of developing PTSD is between 60% and 80% (Harvey, J Consult Clin Psych. 1999:67:995-998).
Selective serotonin reuptake inhibitors (SSRIs), the most commonly used and only U.S. Food and Drug Administration-approved treatment for PTSD, have shown a modest treatment effect of between 0.3 and 0.5. (Brady et al, JAMA, 2000, 283:1837-1844; Davidson et al., Arch Gen Psychiatry 2001:58:485-492; and Marshall et al., Am J Psychiatry, 2001: 158:1982-1988). Consequently, many of these patients remain quite ill and impaired in their functioning, even after numerous trials and years on medication treatment. Despite the common occurrence of this disorder, pharmacologic treatment studies are limited.
Depression, anxiety, and stress share biological pathways and symptoms of these conditions frequently occur together in clinical practice. Recent estimates show that close to 60% of patients with Major Depressive Disorder (MDD) have a co-morbid anxiety disorder (Silverstone et al., Can J Psychiatry 2003:48:675-680). In almost every diagnostic category of anxiety disorders, nearly 50% of patients are reported to have a co-morbid depressive disorder (Dunner, Depress Anxiety. 2001; 13:57-71).
Fava et al. (J Affect Disord 2000; 59:119-126), reported that Generalized Anxiety Disorder preceded depression 63% of the time. Post Traumatic Stress Disorder (PTSD) has been shown to precede Major Depressive Disorder one half to two thirds of the time (Kaufman and Chamey, Depress Anxiety. 2000; 12 Suppl 1:69-76). Time trend analysis of the U.S. National Comorbidity Survey shows that the onset of an anxiety disorder results in a fairly persistent risk for the development of MDD and that an increased risk of MDD persists for many years after the onset of an anxiety disorder.
Patients with co-occurring depression and anxiety disorders are common and tend to experience greater functional impairment, higher symptom severity and poorer prognosis than those with either disorder alone (Kaufman and Chamey, Depress Anxiety 2000; 12, Supp. 1:69-76; Lecrubier, J Clin Psychiatry. 1998; 59 Suppl 17:33-38; Lecrubier, J Clin Psychiatry. 1998; 59 Suppl 8:11-4; discussion 15-16). As a result, these patients often require more aggressive and multiple treatment modalities in order to effectively treat both conditions. Dehydroepiandrosterone (DHEA) is a compound that has been shown to have actions on certain psychiatric conditions. One open series, (Wolkowitz et al. Biol Psychiatry 1997; 41:311-318) and 3 placebo-controlled, double-blind, randomized trials (Schmidt et al., Arch Gen Psychiatry 2005; 62:154-162, Wolkowitz et al. Am J Psychiatry 1999; 156:646-649, Bloch et al. Biol Psychiatry 1999; 45:1533-1541) have supported the effectiveness of DHEA in midlife major and minor depression or dysthymia. Several recent reviews have also discussed data on DHEA to enhance memory, cognition, sexual functioning, and well-being in healthy elderly individuals and in patients with adrenal insufficiency. (Gurnell et al. Eur J Endocrinol 2001; 145:103-106, Yen S S C., PNAS 2001:98:8167-8169). Unfortunately, DHEA is aromatized into testosterone or estrogen and therefore has risks associated with its use.
DHEA appears to have similar actions on both males and females. The study by Rasmusson et al. (Neuropsychopharmacology 2004; 29:1546-1557) of 13 women with chronic PTSD showed that a higher level of DHEA in response to activation by adrenocorticotropic hormone was associated with less severe PTSD symptomotology and that a higher ratio of peak DHEA to cortisol was associated with less-severe negative mood symptoms. Morgan and colleagues' study of 25 elite special operations solders during prolonged and extreme training stress showed that subjects who reported fewer symptoms of dissociation and exhibited superior military performance had significantly higher ratios of DHEA sulfate to cortisol (Morgan et al., Arch Gen Psychiatry 2004; 61:819-825).
DHEA and its sulfate ester (DHEA-S) are produced in human adrenal glands beginning at about 7 years of age. DHEA-S is the most abundant steroid (14 mg/l) in the blood plasma of humans at age 20 to 30 years, and decreases steadily to about one-tenth that concentration at age 70 to 80 years. Because levels of DHEA and general health decline with age, it has been postulated that DHEA replacement may help to maintain a more youthful state. DHEA is an intermediate in the biologic conversion of cholesterol to androgens and estrogens. DHEA can be hydroxylated in tissues to produce both 7 alpha and 7 beta-hydroxy DHEA, which in turn can be oxidized at the 7 position. Overall well being, particularly in the aged, has been reported to improve with DHEA supplementation, with possible benefits in muscle strength, mood ratings, and memory performance.
Similarly, anxiety and depression can present with multiple overlapping symptoms and stem from the same biological correlates. Treatment is guided by the clinical presentation of these illnesses and our evolving understanding of their pathophysiology. We now know that when treating an individual with co-morbid conditions, effective treatment requires remission of not only the primary disorder but of the co-morbid condition as well.
What is needed therefore are novel treatment methods and compositions to treat symptoms of psychiatric disorders such as stress disorders, anxiety disorders and depression. Ideal compounds are safe and effective with few, if any, side effects.